In this phase 1 open-label study, we assessed the relative bioavailability of a prototype tablet formulation of TAK-931, a cell division cycle 7 kinase inhibitor, in reference to the current powder-in-capsule (PIC) formulation in patients with advanced solid tumors for whom no effective standard treatment was available. Adult patients were randomized 1:1 in a crossover fashion to receive one dose of TAK-931 80 mg PIC on Day 1 and one dose of TAK-931 80 mg tablet on Day 3 (or the reverse sequence), followed by TAK-931 50 mg PIC once daily (QD) for 12 days starting from Day 5, before a 7-day rest period (Cycle 0). From Cycle 1, all patients received 50 mg PIC QD on Days 1–14 followed by a 7-day rest period. Twenty patients were enrolled. Median T_max was achieved approximately 2 h post-dose of TAK-931 80 mg for both tablet and PIC. Geometric mean C_max, AUC exposures, and T_1/2z of TAK-931 were similar for both formulations. Geometric mean C_max, AUC_last, and AUC_inf ratios were 0.936 (90% confidence interval [CI]: 0.808–1.084), 1.004 (90% CI: 0.899–1.120), and 1.007 (90% CI: 0.903–1.123), respectively, for TAK-931 tablet in reference to PIC. Discontinuation of TAK-931 due to treatment-emergent adverse events (TEAEs) occurred in 1 patient. Four (20%) patients experienced a serious TEAE; none were considered related to TAK-931. Pharmacokinetics and systemic exposure profiles were similar following administration of both formulations, supporting the transition from PIC to tablet in the clinical development of TAK-931. (Trial registration number ClinicalTrials.gov NCT03708211. Registration date October 12, 2018).

在这项 1 期开放标签研究中，我们评估了 TAK-931（一种细胞分裂周期 7 激酶抑制剂）原型片剂制剂的相对生物利用度，参考了晚期晚期患者的当前粉末胶囊 (PIC) 制剂没有有效标准治疗的实体瘤。成年患者以交叉方式按 1:1 随机分配，在第 1 天接受一剂 TAK-931 80 mg PIC，在第 3 天接受一剂 TAK-931 80 mg 片剂（或相反顺序），随后接受 TAK-931从第 5 天开始，在 7 天休息期（第 0 周期）之前，每天一次 (QD) 50 mg PIC，持续 12 天。从第 1 周期开始，所有患者在第 1-14 天接受 50 mg PIC QD，然后休息 7 天。招募了 20 名患者。中值 T_最大值对于片剂和 PIC，在服用 TAK-931 80 mg 后约 2 小时达到。两种制剂的 TAK-931几何平均 C _max、AUC 暴露量和 T _1/2z相似。几何平均数 C _max、 AUC _last和 AUC _infTAK-931 片剂的比率分别为 0.936（90% 置信区间 [CI]：0.808–1.084）、1.004（90% CI：0.899–1.120）和 1.007（90% CI：0.903–1.123）图片。1 名患者因治疗中出现的不良事件 (TEAE) 而停用 TAK-931。四名 (20%) 患者经历了严重的 TEAE；没有一个被认为与 TAK-931 相关。两种制剂给药后的药代动力学和全身暴露情况相似，支持在 TAK-931 的临床开发中从 PIC 过渡到片剂。（试验注册号 ClinicalTrials.gov NCT03708211。注册日期 2018 年 10 月 12 日）。